Questioning the HDL Hypothesis

For decades, the relationship between cholesterol and heart health seemed to be black and white: High levels of “bad” or “lousy” LDL cholesterol raised the risk for heart disease. High levels of “good” HDL or “healthy” cholesterol reduced it by removing cholesterol from artery walls. The belief has been so solid that doctors routinely prescribed drugs like niacin to help raise HDL levels.

But research over the last few years is challenging this dogma and calling such entrenched practices into question. First a large clinical trial involving 3414 patients showed that taking a high-dose, extended release form of niacin in conjunction with a statin offered no additional benefit over taking the statin alone in reducing heart-related complications.

More doubts emerged with a 2012 Lancet study looking at genetic variants that confer higher HDL levels, including the endothelial lipase gene that only affects HDL. The theory was that if HDL lowers heart disease risk, then those who produce more HDL should be at lower risk. But researchers found no relationship between the gene variation and heart disease. They drew a similar conclusion when looking at 14 other gene mutations that affect HDL levels.

Developing other agents for raising HDL cholesterol has also proved to be problematic. For example, the compound, anacetrapib, now in late-stage clinical trials, looks promising. But since it also lowers LDL cholesterol, researchers can’t conclude that its effects are related to raising HDL. Trials of similar drugs in the same class of medications (evacetrapib, torcetrapib, and dalcetrapib) failed to show a cardiovascular benefit despite very large increases in HDL and were stopped early. At present there are no clear guidelines for targeting HDL, due to a lack of consistent data on outcomes.

Most recently scientists compared genomes of people with high HDL cholesterol to those of a control group with low HDL. Their study looked for mutations in a protein called SR-BI, responsible for binding to HDL cholesterol and facilitating its movement from the blood to the liver. As predicted, people with the gene variant had higher levels of HDL. Yet they had a higher risk for heart disease, not a lower one.

Increasingly it looks possible that although HDL is associated with lower cardiovascular risk, it may not be responsible for this effect. Instead HDL may be a marker for something else that is protecting the heart, a by-product of exercise or a heart-healthy diet, for example.

LDL cholesterol’s record and reputation remains solid. Lowering levels of it through exercise, diet, and statins decreases the risk for clogged arteries and dangerous heart events.

But the relationship between HDL and heart disease is murkier and more controversial, in part because HDL is very complex. Researchers are now looking beyond measuring the amount of HDL and are seeking to understand and measure the functionality of HDL cholesterol. Although some HDL may improve artery health, other HDL may not. Additionally, levels of inflammation may affect HDL’s role.

Until more is learned, HDL still has important value. Low HDL can cue doctors to order advanced blood tests and encourage patients to become more aggressive in lowering their LDL cholesterol—something everyone can agree is heart healthy—and reduce known risk factors associated with low HDL, such as smoking and undiagnosed or uncontrolled diabetes.